Search

Hospital annual volumes for EVAR and OSR were calculated separately, averaged across years, and volume quartiles were created among 4 groups (intact/ruptured EVAR, intact/ruptured OSR). Risk-adjusted analysis of volume-outcome impact on in-hospital mortality after EVAR and open repair of intact and ruptured abdominal aortic aneurysms.A and B, Risk-adjusted mortality outcomes for intact and ruptured EVAR by annual hospital volume quartile. These findings have important consequences on hospital accreditation and care regionalization to improve overall AAA repair mortality outcomes internationally. [Extracted from the article]

Empirical research is an important methodology for the study of conceptual modeling practices. The recently published article "Representing Part-Whole Relations in Conceptual Modeling: An Empirical Evaluation" (Shanks et al. 2008) uses the lens of ontology to study a relatively sophisticated aspect of conceptual modeling practice, the representation of aggregation and composition. It contends that some analysts argue that a composite should be represented as a relationship while others argue that a composite should be represented as an entity. We find no evidence of such a dispute in the data modeling literature. We observe that composites are objects. By definition, all object-types should be represented as entities. Therefore, using the relationship construct to represent composites should not be seen as a viable alternative. Additionally, we found significant conceptual and methodological issues within the study that call its conclusions into question. As a way to offer insight into the requisite methodological procedures for research in this area, we conducted two experiments that both explicate and address the issues raised. Our results call into question the utility of using ontology as a foundation for conceptual modeling practice. Furthermore, they suggest a contrary but at least equally plausible explanation for the results reported by Shanks et al. In conducting this work we hope to encourage dialogue that will be beneficial for future endeavors aimed at identifying, developing, and evaluating appropriate foundations for the discipline of conceptual modeling. [ABSTRACT FROM AUTHOR]

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes. [ABSTRACT FROM AUTHOR]

An introduction is presented to the articles published in this issue.

Ad hoc query formulation is an important task in effectively utilizing organizational data resources. To facilitate this task, managers and casual end-users are commonly presented with database views expressly constructed for their use. Differences in the way in which things, states, and events are represented in such views can affect a user's ability to understand the database, potentially leading to different levels of performance (i.e., accuracy, confidence, and prediction of the accuracy of their queries). An experiment was conducted over the Internet involving 342 subjects from 6 universities in North America and Europe to investigate these effects. When presented with an event-based view, subjects expressing low or very low comfort levels in reading entity-relationship diagrams expressed confidence that better predicted query accuracy although there were no significant differences in actual query accuracy or level of confidence expressed. [ABSTRACT FROM AUTHOR]

Two paradigms characterize much of the research in the Information Systems discipline: behavioral science and design science. The behavioral science paradigm seeks to develop and verify theories that explain or predict human or organizational capabilities by creating new and innovative artifacts. Both paradigms are foundational to the IS discipline, positioned as it is at the confluence of people, organizations, and technology. Our objective is to describe the performance of design-science research in Information Systems via a concise conceptual framework and clear guidelines for understanding, executing, and evaluating the research. In the design-science paradigm, knowledge and understanding of a problem domain and its solution are achieved in the building and application of the designed artifact. Three recent exemplars in the research literature are used to demonstrate the application of these guidelines. We conclude with an analysis of the challenges of performing high-quality design-science research in the context of the broader IS community. [ABSTRACT FROM AUTHOR]

The granuloma plays a critical role in the host immune response to Mycobacterium tuberculosis, containing the organism and confining it in a latent state in most infected individuals. Indeed, approximately one-third of the world’s population has latent M. tuberculosis infection. However, over the past decade, the human immunodeficiency virus type 1 (HIV-1) pandemic has profoundly affected the incidence and clinicopathological features of tuberculosis. This review examines the immunological mechanisms whereby HIV-1 impairs the establishment, maintenance and function of the tuberculous granuloma. [Copyright &y& Elsevier]

Background: There is wide variation in stress test utilization before major vascular surgery and adherence to practice guidelines is unclear. We defined rates of stress test compliance at our institution and led a quality improvement initiative to improve compliance with American Heart Association (ACC/AHA) guidelines. Methods: We implemented a stress testing order set in the electronic medical record at one tertiary hospital. We reviewed all patients who underwent elective, major vascular surgery in the 6 months before (Jan 1, 2022 – Jul 1, 2022) and 6 months after (Aug 1, 2022 – Jan 31, 2023) implementation. We studied stress test guideline compliance, changes in medical or surgical management, and major adverse cardiac events (MACE). Results: Before order set implementation, 37/122 patients (30%) underwent stress testing within the past year (29 specifically ordered preoperatively) with 66% (19/29) guideline compliance. After order set implementation, 50/173 patients (29%) underwent stress testing within the past year (41 specifically ordered preoperatively) with 80% (33/41) guideline compliance. In the pre- and postimplementation cohorts, stress testing led to a cardiovascular medication change or preoperative coronary revascularization in 24% (7/29) and 27% (11/41) of patients, and a staged surgery or less invasive anesthetic strategy in 14% (4/29) and 4.9% (2/41) of patients, respectively. All unindicated stress tests were surgeon-ordered and none led to a change in management. There was no change in MACE after order set implementation. Conclusions: Electronic medical record-based guidance of perioperative stress testing led to a slight decrease in overall stress testing and an increase in guideline-compliant testing. Our study highlights a need for improved preoperative cardiovascular risk assessment prior to major vascular surgery, which may eliminate unnecessary testing and more effectively guide perioperative decision-making. [ABSTRACT FROM AUTHOR]

The article discusses the guidelines set by the editorial board of the journal regarding the publication and submission of survey papers.

Structuring database records by considering data item usage can yield substantial efficiencies in the operating cost of database systems. However, since the number of possible physical record structures for database of practical significance is enormous, and their evaluation is extremely complex, determining efficient record structures by full enumeration is generally infeasible. This paper discusses the techniques of mathematical clustering, iterative grouping refinement, mathematical programming, and hierarchic aggregation, which can be used to quickly determine efficient record structures for large, shared databases. [ABSTRACT FROM AUTHOR]

The article presents information about the editorial policy of the periodical ACM Computing Surveys. This policy document is intended to cover most of the commonly asked questions and frequently occurring problems in the process of handling papers and editing Computing Surveys. Good survey papers often borrow concepts from both surveys and tutorials. The main differences between the two are emphasis and audience. In practice, most papers published in Surveys combine the two approaches, they survey a range of material and explain the underlying concepts. They have no limitations on which subjects to emphasize in Surveys. Historically, Surveys has closely reflected the interests of ACM's members. Analysis of published papers by subject and page count correlates well with relative sizes of memberships in various special interests groups. They publish any survey or tutorial paper on any topic of interest to ACM, subject to reviewing standards. But there are some important differences between Surveys and the other ACM journals.

This case illustrates the feasibility of endovascular treatment for chronic venous insufficiency attributable to congenital atresia of the infrarenal inferior vena cava (IVC). Three-dimensional computed tomography (CT) venography can elucidate alternate sites of drainage and indentify other venous pathology, such as dominant stenoses that may be amenable to venoplasty and/or stent placement. [ABSTRACT FROM AUTHOR]

Discusses the need for information systems research to combine the creativity and precision of design science with the empiricism and discipline of behavioral science. Goal of information systems research; Overview of the behavioral-science paradigm and the design-science paradigm; Conceptual framework for understanding, executing and evaluating IS research that combines the behavioral- and design-science paradigms.

The article discusses research papers concerning information technology and information systems published within the issue.

Background: Despite improved surgical approaches for chronic limb‐threatening ischemia (CLTI), amputation rates remain high and contributing tissue‐level factors remain unknown. The purpose of this study was twofold: (1) to identify differences between the healthy adult and CLTI limb muscle proteome, and (2) to identify differences in the limb muscle proteome of CLTI patients prior to surgical intervention or at the time of amputation. Methods and results: Gastrocnemius muscle was collected from non‐ischemic controls (n = 19) and either pre‐interventional surgery (n = 10) or at amputation outcome (n = 29) CLTI patients. All samples were subjected to isobaric tandem‐mass‐tag‐assisted proteomics. The mitochondrion was the primary classification of downregulated proteins (> 70%) in CLTI limb muscles and paralleled robust functional mitochondrial impairment. Upregulated proteins (> 38%) were largely from the extracellular matrix. Across the two independent sites, 39 proteins were downregulated and 12 upregulated uniformly. Pre‐interventional CLTI muscles revealed a robust upregulation of mitochondrial proteins but modest functional impairments in fatty acid oxidation as compared with controls. Comparison of pre‐intervention and amputation CLTI limb muscles revealed mitochondrial proteome and functional deficits similar to that between amputation and non‐ischemic controls. Interestingly, these observed changes occurred despite 62% of the amputation CLTI patients having undergone a prior surgical intervention. Conclusions: The CLTI proteome supports failing mitochondria as a phenotype that is unique to amputation outcomes. The signature of pre‐intervention CLTI muscle reveals stable mitochondrial protein abundance that is insufficient to uniformly prevent functional impairments. Taken together, these findings support the need for future longitudinal investigations aimed to determine whether mitochondrial failure is causally involved in amputation outcomes from CLTI. [ABSTRACT FROM AUTHOR]

Hand dysfunction is a common observation after arteriovenous fistula (AVF) creation for hemodialysis access and has a variable clinical phenotype; however, the underlying mechanism responsible is unclear. Grip strength changes are a common metric used to assess AVF-associated hand disability but has previously been found to poorly correlate with the hemodynamic perturbations post-AVF placement implicating other tissue-level factors as drivers of hand outcomes. In this study, we sought to test if expression of a mitochondrial targeted catalase (mCAT) in skeletal muscle could reduce AVF-related limb dysfunction in mice with chronic kidney disease (CKD). Male and female C57BL/6J mice were fed an adenine-supplemented diet to induce CKD prior to placement of an AVF in the iliac vascular bundle. Adeno-associated virus was used to drive expression of either a green fluorescent protein (control) or mCAT using the muscle-specific human skeletal actin (HSA) gene promoter prior to AVF creation. As expected, the muscle-specific AAV-HSA-mCAT treatment did not impact blood urea nitrogen levels (P = 0.72), body weight (P = 0.84), or central hemodynamics including infrarenal aorta and inferior vena cava diameters (P > 0.18) or velocities (P > 0.38). Hindlimb perfusion recovery and muscle capillary densities were also unaffected by AAV-HSA-mCAT treatment. In contrast to muscle mass and myofiber size which were not different between groups, both absolute and specific muscle contractile forces measured via a nerve-mediated in-situ preparation were significantly greater in AAV-HSA-mCAT treated mice (P = 0.0012 and P = 0.0002). Morphological analysis of the post-synaptic neuromuscular junction uncovered greater acetylcholine receptor cluster areas (P = 0.0094) and lower fragmentation (P = 0.0010) in AAV-HSA-mCAT treated mice. Muscle mitochondrial oxidative phosphorylation was not different between groups, but AAV-HSA-mCAT treated mice had lower succinate-fueled mitochondrial hydrogen peroxide emission compared to AAV-HSA-GFP mice (P < 0.001). In summary, muscle-specific scavenging of mitochondrial hydrogen peroxide significantly improves neuromotor function in mice with CKD following AVF creation. [ABSTRACT FROM AUTHOR]

We present a case of cardiogenic shock secondary to refractory polymorphic ventricular tachycardia associated with coronary ischemia resulting in cardiac arrest. Following the return of spontaneous circulation, the patient was cannulated for peripheral venoarterial extracorporeal membrane oxygenation (V-A ECMO) in anticipation of high-risk "protected" percutaneous coronary intervention (PCI). Under full V-A ECMO support, inotropes and vasopressors were weaned off, and the patient underwent uneventful PCI of left circumflex and obtuse marginal lesions. After 48 hours, the patient was decannulated and could be discharged home alive 16 days after his initial cardiac arrest. [ABSTRACT FROM AUTHOR]

Objective: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) is an important data source for observational studies. While there are guides to ensure appropriate study reporting, there has been no evaluation of NSQIP studies in vascular surgery. We sought to evaluate the adherence of vascular-surgery related NSQIP studies to best reporting practices. Methods: In January 2022, we queried PubMed for all vascular surgery NSQIP studies. We used the REporting of studies Conducted using Observational Routinely-collected Health Data (RECORD) statement and the JAMA Surgery (JAMA-Surgery) checklist to assess reporting methodology. We also extracted the Journal Impact Factor (IF) of each article. Results: One hundred and fifty-nine studies published between 2002 and 2022 were identified and analyzed. The median score on the RECORD statement was 6 out of 8. The most commonly missed RECORD statement items were describing any validation of codes and providing data cleaning information. The median score on the JAMA-Surgery checklist was 2 out of 7. The most commonly missed JAMA-Surgery checklist items were identifying competing risks, using flow charts to help visualize study populations, having a solid research question and hypothesis, identifying confounders, and discussing the implications of missing data. We found no difference in the reporting methodology of studies published in high vs low IF journals. Conclusion: Vascular surgery studies using NSQIP data demonstrate poor adherence to research reporting standards. Critical areas for improvement include identifying competing risks, including a solid research question and hypothesis, and describing any validation of codes. Journals should consider requiring authors use reporting guides to ensure their articles have stringent reporting methodology. [ABSTRACT FROM AUTHOR]

For end-stage kidney disease (ESKD) patients, hemodialysis requires durable vascular access which is often surgically created using an arteriovenous fistula (AVF). However, some ESKD patients that undergo AVF placement develop access-related hand dysfunction (ARHD) through unknown mechanisms. In this study, we sought to determine if changes in the serum metabolome could distinguish ESKD patients that develop ARHD from those that have normal hand function following AVF creation. Forty-five ESKD patients that underwent first-time AVF creation were included in this study. Blood samples were obtained pre-operatively and 6-weeks post-operatively and metabolites were extracted and analyzed using nuclear magnetic resonance spectroscopy. Patients underwent thorough examination of hand function at both timepoints using the following assessments: grip strength manometry, dexterity, sensation, motor and sensory nerve conduction testing, hemodynamics, and the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Nineteen of the forty-five patients displayed overt weakness using grip strength manometry (P < 0.0001). Unfortunately, the serum metabolome was indistinguishable between patients with and without weakness following AVF surgery. However, a significant correlation was found between the change in tryptophan levels and the change in grip strength suggesting a possible role of tryptophan-derived uremic metabolites in post-AVF hand-associated weakness. Compared to grip strength, changes in dexterity and sensation were smaller than those observed in grip strength, however, post-operative decreases in phenylalanine, glycine, and alanine were unique to patients that developed signs of motor or sensory disability following AVF creation. [ABSTRACT FROM AUTHOR]

This section introduces a series of articles on computing surveys.

The article presents an introduction to various articles published in this issue. Computer applications have become extremely complex. The cost of developing software from scratch has risen dramatically. One approach to reducing the cost of software development is to create software systems from existing software. That is, to reuse rather than rewrite software components. Case technologies and various development environments, including object-oriented and very high-level languages, provide a variety of mechanisms for managing and using libraries of software components. For example, application generators maintain program skeletons for various types of program modules. The software developer fills in the parameters to create a specific application. In Software Reuse, Charles W. Krueger surveys software reuse approaches. He presents a taxonomy characterizing each approach by its reusable artifacts and by the way in which the approach addresses the problems of describing, selecting, customizing and integrating those components.

Artificial intelligence has become one of the most viable and glamorous areas of computer science. Science fiction has robots acting in an almost indistinguishable manner from humans. Object recognition can be a challenging task, even for humans. Children's playbooks often includes puzzles in which child is to recognize a picture within a drawing of a schoolyard or some other scene. Difficulties revolve around the fact that the child's mental image of the picture may not correspond direct to the representation in the scene. With automated object recognition, a general model of the object must be defines and algorithms developed to search for the model with in the scene. Such models are analogous to a mental image used by a human. To be effective, the model must be general enough to allow for different views and positioning of the objects and be able to differentiate the object from other, entangling, objects. Furthermore, these algorithms effectively apply the model to the given image.

The objective of the present study was to determine if treatment with N-acetylcysteine (NAC) could reduce access-related limb dysfunction in mice. Male and female C57BL6J mice were fed an adenine-supplemented diet to induce chronic kidney disease (CKD) prior to the surgical creation of an arteriovenous fistula (AVF) in the iliac vascular bundle. AVF creation significantly increased peak aortic and infrarenal vena cava blood flow velocities, but NAC treatment had no significant impact, indicating that fistula maturation was not impacted by NAC treatment. Hindlimb muscle and paw perfusion recovery and muscle capillary density in the AVF limb were unaffected by NAC treatment. However, NAC treatment significantly increased the mass of the tibialis anterior (P = 0.0120) and soleus (P = 0.0452) muscles post-AVF. There was a significant main effect of NAC treatment on hindlimb grip strength at postoperative day 12 (POD 12) (P = 0.0003), driven by significantly higher grip strength in both male (P = 0.0273) and female (P = 0.0031) mice treated with NAC. There was also a significant main effect of NAC treatment on the walking speed at postoperative day 12 (P = 0.0447), and post hoc testing revealed an improvement in NAC-treated male mice (P = 0.0091). The area of postsynaptic acetylcholine receptors (P = 0.0263) and motor endplates (P = 0.0240) was also increased by NAC treatment. Interestingly, hindlimb skeletal muscle mitochondrial oxidative phosphorylation trended higher in NAC-treated female mice but was not statistically significant (P = 0.0973). Muscle glutathione levels and redox status were not significantly impacted by NAC treatment in either sex. In summary, NAC treatment attenuated some aspects of neuromotor pathology in mice with chronic kidney disease following AVF creation. NEW & NOTEWORTHY Hemodialysis via autogenous arteriovenous fistula (AVF) is the preferred first-line modality for renal replacement therapy in patients with end-stage kidney disease. However, patients undergoing AVF surgery frequently experience a spectrum of hand disability symptoms postsurgery including weakness and neuromotor dysfunction. Unfortunately, no treatment is currently available to prevent or mitigate these symptoms. Here, we provide evidence that daily N-acetylcysteine supplementation can attenuate some aspects of limb neuromotor function in a preclinical mouse model of AVF. [ABSTRACT FROM AUTHOR]

Background: Chronic limb-threatening ischemia (CLTI) can be associated with dismal outcomes but there are limited real-world data to further define the impact of end-stage kidney disease (ESKD) on outcomes nationally in this subset of patients. We sought to characterize national patterns of inpatient treatment of CLTI and compare outcomes in patients without ESKD. Methods: The National Inpatient Sample was queried from 2015-2018 for all hospital admissions including treatment for CLTI. Mixed-effects linear and logistic regression models were used to estimate the effect of ESKD on outcomes and treatment choice. Results: We identified 11 652 hospital admissions with CLTI alone and 2705 with CLTI + ESKD. Hospital admissions with CLTI + ESKD patients included patients who were younger (66 vs 69 years, P <.0001), less likely to be white (39% vs 63%, P <.0001), and more likely to reside in lower income large metropolitan areas. Admissions for CLTI + ESKD patients had a lower likelihood of open arterial reconstruction (OR.40, P <.0001) and a higher likelihood of endovascular revascularization or major limb amputation (OR 1.70, P <.0001). Admissions for CLTI + ESKD also had a 4.5- and 1.5-fold higher odds of in-hospital death and complications. These findings were associated with a longer LOS (P <.0001), increased probability of discharge to rehabilitation facility (50% vs 41%, P <.0001), and greater hospital charges (median, $107 K vs $85 K, P <.0001). Conclusions: Compared to hospital admissions for patients without ESKD, admissions for patients with CLTI + ESKD demonstrated distinctive demographic characteristics, a lower likelihood of open revascularization and a higher likelihood of endovascular revascularization and major limb amputation. Chronic limb-threatening ischemia + ESKD hospital admissions showed worse overall outcomes and greater resource utilization compared to CLTI admissions without ESKD. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue, including one by Joan Peckham and Fred Maryanski on the generic constructs used to represent the semantics of data to be used in a database, and another by Michael V. Manino, Paicheng Chu and Thomas Sager on a tutorial describing the instances that make up a database.

End-stage kidney disease, the most advanced stage of chronic kidney disease (CKD), requires renal replacement therapy or kidney transplant to sustain life. To accomplish durable dialysis access, the creation of an arteriovenous fistula (AVF) has emerged as a preferred approach. Unfortunately, a significant proportion of patients that receive an AVF experience some form of hand dysfunction; however, the mechanisms underlying these side effects are not understood. In this study, we used nuclear magnetic resonance spectroscopy to investigate the muscle metabolome following iliac AVF placement in mice with CKD. To induce CKD, C57BL6J mice were fed an adenine-supplemented diet for 3 wk and then randomized to receive AVF or sham surgery. Two weeks following surgery, the quadriceps muscles were rapidly dissected and snap frozen for metabolite extraction and subsequent nuclear magnetic resonance analysis. Principal component analysis demonstrated clear separation between groups, con- firming a unique metabolome in mice that received an AVF. AVF creation resulted in reduced levels of creatine, ATP, and AMP as well as increased levels of IMP and several tricarboxylic acid cycle metabolites suggesting profound energetic stress. Pearson correlation and multiple linear regression analyses identified several metabolites that were strongly linked to measures of limb function (grip strength, gait speed, and mitochondrial respiration). In summary, AVF creation generates a unique metabolome profile in the distal skeletal muscle indicative of an energetic crisis and myosteatosis. [ABSTRACT FROM AUTHOR]

Preclinical animal models of chronic kidney disease (CKD) are critical to investigate the underlying mechanisms of disease and to evaluate the efficacy of novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (Nx) CKD models in mice. Male and female 10-wk-old C57BL/6J mice (n = 5–9 mice/sex/group) were randomly allocated to CKD groups (0.2−0.15% adenine-supplemented diet or 5/6 Nx surgery) or the corresponding control groups (casein diet or sham surgery). Following the induction of CKD, the glomerular filtration rate was reduced to a similar level in both adenine and 5/6 Nx mice (adenine diet-fed male mice: 81.1 ± 41.9 µL/min vs. 5/6 Nx male mice: 160 ± 80.9 µL/min, P = 0.5875; adenine diet-fed female mice: 112.9 ± 32.4 µL/min vs. 5/6 Nx female mice: 107.0 ± 45.7 µL/min, P = 0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e., p-cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas Ca2+ homeostasis was disturbed in male mice with both CKD models. Compared with control mice, muscle mass and myofiber cross-sectional areas of the extensor digitorum longus and soleus muscles were ∼18−24% smaller in male CKD mice regardless of the model but were not different in female CKD mice (P > 0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19−24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy. However, the adenine diet model demonstrated superior performance with regard to mortality (∼20−50% mortality for 5/6 Nx vs. 0% mortality for the adenine diet, P < 0.05 for both sexes) compared with the 5/6 Nx surgical model. [ABSTRACT FROM AUTHOR]

This article discusses the management of post-surgical biliary leaks (PSBL), which are complications that can occur after liver or biliary tract surgeries. The study focuses on the use of endoscopic retrograde cholangiopancreatography (ERCP) and a percutaneous transhepatic approach called Rendez Vous as treatment options for PSBL. The study found that these procedures were safe and effective, with a high rate of clinical success. Stent positioning, particularly leak-bridging stents, was recommended to enhance treatment efficacy. The article also mentions that adverse events were reported in 10% of cases, but none were severe. [Extracted from the article]

Here we report an unusual case of primary systemic amyloidosis. The cutaneous lesions were polymorphic and included involvement of both external auditory canals. The visceral involvement was covert. Mapping of amyloid deposits was performed using scintigraphy with technetium-99m (V) dimercaptosuccinic acid ([[sup99m]Tc (V)]] DMSA). Therapy with melphalan, prednisone and colchicine resulted in considerable improvement. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) leads to increased skeletal muscle fatigue, weakness, and atrophy. Previous work has implicated mitochondria within the skeletal muscle as a mediator of muscle dysfunction in CKD; however, the mechanisms underlying mitochondrial dysfunction in CKD are not entirely known. The purpose of this study was to define the impact of uremic metabolites on mitochondrial energetics. Skeletal muscle mitochondria were isolated from C57BL/6N mice and exposed to vehicle (DMSO) or varying concentrations of uremic metabolites: indoxyl sulfate, indole- 3-acetic-acid, L-kynurenine, and kynurenic acid. A comprehensive mitochondrial phenotyping platform that included assessments of mitochondrial oxidative phosphorylation (OXPHOS) conductance and respiratory capacity, hydrogen peroxide production (JH2O2), matrix dehydrogenase activity, electron transport system enzyme activity, and ATP synthase activity was employed. Uremic metabolite exposure resulted in a ~25-40% decrease in OXPHOS conductance across multiple substrate conditions (P < 0.05, n = 5-6/condition), as well as decreased ADP-stimulated and uncoupled respiratory capacity. ATP synthase activity was not impacted by uremic metabolites; however, a screen of matrix dehydrogenases indicated that malate and glutamate dehydrogenases were impaired by some, but not all, uremic metabolites. Assessments of electron transport system enzymes indicated that uremic metabolites significantly impair complex III and IV. Uremic metabolites resulted in increased JH2O2 under glutamate/malate, pyruvate/malate, and succinate conditions across multiple levels of energy demand (all P < 0.05, n = 4/group). Disruption of mitochondrial OXPHOS was confirmed by decreased respiratory capacity and elevated superoxide production in cultured myotubes. These findings provide direct evidence that uremic metabolites negatively impact skeletal muscle mitochondrial energetics, resulting in decreased energy transfer, impaired complex III and IV enzyme activity, and elevated oxidant production. [ABSTRACT FROM AUTHOR]

We have investigated the immunogenicity in rabbits of native-like, soluble, recombinant SOSIP.664 trimers based on the env genes of four isolates of human immunodeficiency virus type 1 (HIV-1); specifically BG505 (clade A), B41 (clade B), CZA97 (clade C) and DU422 (clade C). The various trimers were delivered either simultaneously (as a mixture of clade A + B trimers) or sequentially over a 73-week period. Autologous, Tier-2 neutralizing antibody (NAb) responses were generated to the clade A and clade B trimers in the bivalent mixture. When delivered as boosting immunogens to rabbits immunized with the clade A and/or clade B trimers, the clade C trimers also generated autologous Tier-2 NAb responses, the CZA97 trimers doing so more strongly and consistently than the DU422 trimers. The clade C trimers also cross-boosted the pre-existing NAb responses to clade A and B trimers. We observed heterologous Tier-2 NAb responses albeit inconsistently, and with limited overall breath. However, cross-neutralization of the clade A BG505.T332N virus was consistently observed in rabbits immunized only with clade B trimers and then boosted with clade C trimers. The autologous NAbs induced by the BG505, B41 and CZA97 trimers predominantly recognized specific holes in the glycan shields of the cognate virus. The shared location of some of these holes may account for the observed cross-boosting effects and the heterologous neutralization of the BG505.T332N virus. These findings will guide the design of further experiments to determine whether and how multiple Env trimers can together induce more broadly neutralizing antibody responses. [ABSTRACT FROM AUTHOR]

R2958 --> 849.8 --> Introduction: Access‐related hand dysfunction (ARHD) such as steal syndrome, neuromotor discoordination, and weakness is prevalent following arteriovenous fistula (AVF) placement in patients with end‐stage renal disease. Despite the progressive increase in symptomatic hemodialysis patients, currently no preclinical animal model exists to examine underlying mechanisms or develop novel therapeutics. Herein, we characterize the hindlimb pathology in a novel mouse model of iliac AVF. Methods: Male 8‐week‐old C57BL/6J mice were randomly assigned to casein‐based chow (CON: n=6) or adenine diet (CKD: n=16) for 3 weeks and glomerular filtration rate (GFR) using FIT‐C inulin clearance was measured. On the day of operation, animals were allocated to receive either left common iliac AVF (CKD_AVF: n=10) or Sham (CON_Sham: n=6, CKD_Sham: n=6) surgery and remained on their original diet throughout the study. Hemodynamic changes, hindlimb grip strength, and gait pattern were assessed prior to and post‐operatively. After two weeks of surgery, the animals were euthanized to assess gastrocnemius mitochondrial respiratory capacity and morphological alterations in tibialis anterior (TA), extensor digitorum longus (EDL), and soleus (SOL) muscles. Results: Animals exposed to adenine diet had impaired kidney function (GFR in CON:441.3±54.2 µL/min vs. CKD: 165.1±118.3 µL/min, p<0.01) prior to surgery. AVF placement increased inferior vena cava diameter (1.4‐fold at POD3 and 1.6‐fold at POD13, P<0.05) and peak velocity (3.3‐fold at POD3 and 3.8‐fold at POD13, P<0.05) when compared to the pre‐surgery values. In contrast to the animals with sham surgery, AVF mice had decreases in perfusion to the ventral paw (‐77.4±17.4% at POD0 and ‐30.7±15.8% at POD13, P<0.05), grip strength (‐58.6±35.1% at POD4 and ‐42.6±30.9% at POD12, P<0.05), and gait speed (‐5.7±5.2cm/sec at POD4, P<0.05 and ‐3.2±4.3 cm/sec at POD12, P=0.10). Gastrocnemius mitochondrial oxidative phosphorylation conductance in response to stress mimic conditions was decreased by both fistula formation and kidney insufficiency (P<0.05). Morphological analysis of limb muscles revealed that AVF mice exhibited ~60% of fibers with central nuclei and had ~35% smaller myofiber cross‐sectional area in TA and SOL muscles compared to CON_Sham (P<0.05) and ~50% lower capillary contacts in TA, EDL, and SOL muscles compared to both sham surgered groups (P<0.05). Conclusion: Iliac AVF creation resulted in central and peripheral hemodynamic alterations, impaired hindlimb neuromotor function, mitochondrial dysfunction, and morphological deformation. Taken together, we identify several key pathophysiological aspects of ARHD in a pre‐clinical model providing a platform to facilitate mechanistic and therapeutic studies aimed to reduce ARHD prevalence in CKD patients. [ABSTRACT FROM AUTHOR]

Background: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-κB inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. Methodology and Principal Findings: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.bgalactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-κB, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. Conclusion: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients' outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation. [ABSTRACT FROM AUTHOR]

Abstract: Little is known about the neutralization properties of HIV-1 in India to optimally design and test vaccines. For this reason, a functional Env clone was obtained from each of ten newly acquired, heterosexually transmitted HIV-1 infections in Pune, Maharashtra. These clones formed a phylogenetically distinct genetic lineage within subtype C. As Env-pseudotyped viruses the clones were mostly resistant to IgG1b12, 2G12 and 2F5 but all were sensitive to 4E10. When compared to a large multi-subtype panel of Env-pseudotyped viruses (subtypes B, C and CRF02_AG) in neutralization assays with a multi-subtype panel of HIV-1-positive plasma samples, the Indian Envs were remarkably complex. With the exception of the Indian Envs, results of a hierarchical clustering analysis showed a strong subtype association with the patterns of neutralization susceptibility. From these patterns we were able to identify 19 neutralization cluster-associated amino acid signatures in gp120 and 14 signatures in the ectodomain and cytoplasmic tail of gp41. We conclude that newly transmitted Indian Envs are antigenically complex in spite of close genetic similarity. Delineation of neutralization-associated amino acid signatures provides a deeper understanding of the antigenic structure of HIV-1 Env. [Copyright &y& Elsevier]

A20 is a NF-κB-dependent gene that has dual inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti-inflammatory function via blockade of NF-κB and NF-κB-dependent proteins ICAM-1 and MCP-1. A20 inhibits SMC proliferation via increased expression of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine- and Fas-mediated apoptosis through a novel NO-dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re-endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined antiinflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to assess the prevalence of cardiorenal risk factors, their management in a routine clinical setting, and the actual achievement of international guideline targets in a large cohort of type 2 diabetic patients with diabetic nephropathy.Research Design and Methods: A multicentric cross-sectional study was performed in the Campania region in Italy to evaluate cardiorenal risk factors and their management in light of international guidelines. Overall, 28,550 diabetic patients were screened in the 21 participating centers; 847 (348 male and 449 female) patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy were recruited.Results: Of these subjects, 749 had microalbuminuria and 98 had macroalbuminuria. Targets for blood pressure, HbA(1c), LDL cholesterol, HDL cholesterol, and triglycerides were reached in, respectively, 17.5, 32.3, 30.7, 47, and 55.2% of the patients. Chronic renal failure (glomerular filtration rate <60 ml/min) was revealed in 41% and anemia in 23.8% of the patients.Conclusions: This is the first study to investigate a large cohort of type 2 diabetic patients with early and moderate diabetic nephropathy strictu sensu. Notably, impaired renal function can be often diagnosed in these patients even in the presence of microalbuminuria. Thus, clinical diagnosis of diabetic nephopathy allows us to identify a group of patients at very high cardiorenal risk, for whom care is really difficult. We suggest that a correct diagnosis of diabetic nephropathy should always be made and that sodium intake and anemia should be routinely evaluated in these patients. [ABSTRACT FROM AUTHOR]

Background: Apoptotic death of renal proximal tubular epithelial cells (RPTECs) is a feature of acute and chronic renal failure. RPTECs are directly damaged by ischemia, inflammatory, and cytotoxic mediators but also contribute to their own demise by up-regulating proinflammatory nuclear factor-kappaB (NF-kappaB)-dependent proteins. In endothelial cells, the Bcl family member A1 and the zinc finger protein A20 have redundant and dual antiapoptotic and anti-inflammatory effects. We studied the function(s) of A1 and A20 in human RPTECs in vitro. Methods: Expression of A1 [reverse transcription-polymerase chain reaction (RT-PCR) and A20 (Northern and Western blot analysis)] in RPTECs was evaluated. A1 and A20 were overexpressed in RPTECs by recombinant adenoviral-mediated gene transfer. Their effect upon inhibitor of NFkappaB alpha (IkappaBalpha) degradation (Western blot), NF-kappaB nuclear translocation [electrophoretic mobility shift assay (EMSA)], up-regulation of intercellular adhesion molecule-1 (ICAM-1) [fluorescence-activated cell sorter (FACS)] and monocyte chemoattractant protein-1 (MCP-1) (Northern blot) and apoptosis [terminal deoxynucleotiddyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)] and FACS analysis of DNA content) was determined. Results: A1 and A20 were induced in RPTECs as part of the physiologic response to tumor necrosis factor (TNF). A20, but not A1, inhibited TNF-induced NF-kappaB activation by preventing IkappaBalpha degradation, hence subsequent up-regulation of the proinflammatory molecules ICAM-1 and MCP-1. Unexpectedly, A20 did not protect RPTECs from TNF and Fas-mediated apoptosis while A1 protected against both stimuli. Coexpression of A1 and A20 in RPTECs achieved additive anti-inflammatory and antiapoptotic cytoprotection. Conclusion: A1 and A20 exert differential cytoprotective effects in RPTECs. A1 is antiapoptotic. A20 is anti-inflammatory via blockade of NF-kappaB. We propose that A1 and A20 are both required for optimal protection of RPTECs from apoptosis (A1) and inflammation (A20) in conditions leading to renal damage. [ABSTRACT FROM AUTHOR]

This study examined the impact of the host inflammatory microenvironment associated with localized tuberculosis (TB) on human immunodeficiency virus type 1 (HIV-1) replication within lymphocytes and macrophages in vivo. Paired plasma and pleural fluid samples from HIV-1-infected individuals with pleural TB (n = 9) were analyzed. Detection of host proteins incorporated into the HIV-1 envelope by immunomagnetic capture analysis provided insight into the phenotype of cells supporting HIV-1 replication. The results indicated that the 4.0-fold greater median HIV-1 load in pleural fluid, compared with median load in plasma (P < .01), was derived in part from viral replication within HLA-DR[sup +] cells, CD26[sup +] lymphocytes, and, importantly, CD14[sup +] macrophages. Greatly increased local concentrations of proinflammatory cytokines and immune activation markers in the pleural space correlated with the virologic findings. In summary, HIV-1 replication was increased at sites of Mycobacterium tuberculosis coinfection within activated cells, including lymphocytes and CD14[sup +] macrophages. [ABSTRACT FROM AUTHOR]

Summary Aim Non-insulin-dependent diabetes mellitus (type 2 diabetes) not responding to dietary treatment alone in patients with non-alcoholic liver cirrhosis is characterized by high postprandial hyperglycaemia. The control of postprandial hyperglycaemia in such patients, is generally achieved by the means of progressively higher doses of insulin, with an increasing risk of hypoglycaemia in the late postprandial period. The aim of this study was to evaluate the use of acarbose for the control of postprandial hyperglycaemia in 100 patients with well-compensated liver cirrhosis and type 2 diabetes treated with insulin. Methods The study was double blind with randomization of treatments into acarbose (52 patients) vs. placebo (48 patients) with parallel branches over a period of 28 weeks. Results All patients tolerated the treatments well and no significant variations in liver function tests were observed (< 5% vs. pretreatment). A significant reduction of several parameters was observed only after acarbose treatment: fasting glycaemia (173 ± 28 vs. 146 ± 19 mg/dl; p < 0.01), postprandial glycaemia (230 ± 24 vs. 148 ± 20 mg/dl; p < 0.01), mean glycaemia (206 ± 20 vs. 136 ± 13 mg/dl; p < 0.01), mean variation (180 ± 14 vs. 51 ± 10 mg/dl; p < 0.01), HbA1c (8.9 ± 0.8 vs. 7.2 ± 0.5; p < 0.05), C-peptide 2 h after a standard meal (4.5 ± 1.9 vs. 2.8 ± 1.7 ng/ml; p < 0.05), whereas the parameters did not change significantly after the placebo. After acarbose treatment a significant increase of intestinal voiding/week (+ 116% vs. + 10%; p < 0.01) and a parallel reduction of blood ammonia levels (- 52 ± 9% vs. - 9 ± 5%; P < 0.01) were observed. Conclusions The results clearly document the good tolerability and the absence of toxic effects of acarbose on liver, due to the lack of both intestinal absorption and hepatic metabolism of the drug at doses in the therapeutic range. In fact,... [ABSTRACT FROM AUTHOR]

Summary Although there is little information from primary or secondary prevention trials on cholesterol-lowering medication in diabetic patients, the reduction of elevated cholesterol is widely recommended for this group. The American Diabetes Association (ADA) recommends drug therapy in diabetic patients if low density lipoprotein (LDL)-cholesterol remains at > 130 mg/dl, or > 100 mg/dl in patients with macroangiopathy, after dietary intervention. When cholesterol-lowering medication is indicated, the choice of the drug must take into account the other lipid abnormalities that are often present and the need to maintain optimal glycaemic control. In the present study we compared the efficacy and safety of the novel HMG-CoA reductase inhibitor atorvastatin at the dose of 10 mg/day with simvastatin , lovastatin and pravastatin at doses of 10, 20 and 20 mg/day, respectively, and placebo, in type 2 diabetic patients with moderate elevation of LDL-cholesterol with or without elevation of triglycerides. All the quoted agents are enzyme inhibitors effective in lowering LDL-cholesterol in humans. The efficacy endpoints were the mean per cent changes in plasma LDL-cholesterol (primary), total cholesterol, triglycerides, and high-density lipoprotein (HDL)-cholesterol concentrations from baseline to the end of treatment (24 weeks). Atorvastatin at a dose of 10 mg/day produced: (1) a significant reduction in LDL-cholesterol (- 37%) in comparison with equivalent doses of simvastatin (- 26%), pravastatin (- 23%), lovastatin (- 21%), and placebo (- 1%); (2) HDL-cholesterol increases (7.4%) comparable to or greater than those obtained with simvastatin (7.1%), pravastatin (3.2%), lovastatin (7.21%), and placebo (- 0.5%); (3) a significantly greater reduction in total cholesterol (- 29%) than that obtained with simvastatin (- 21%), pravastain (- 16%), lovastatin (- 18%), and placebo (1%); and (4) a significantly greater reduction in triglycerides than that obtained with... [ABSTRACT FROM AUTHOR]

Examines the correlation between human immunodeficiency virus type 1 (HIV-1) RNA levels in the female genital tract and immune activation associated with ulceration of the cervix. Effect of treatment of cervical dysplasia on HIV-1 load; Effect of treatment of cervical dysplasia on concentrations of tumor necrosis factor (TNF)-alpha and interleukin-6; Effect of treatment on macrophage and lymphocyte pools in the genital tract.

Objective: To evaluate the effectiveness and safety of tolrestat, an aldose-reductase inhibitor, in patients with mild diabetic autonomic and peripheral neuropathy.Design: Randomized, placebo-controlled, double-blind 52-week trial.Setting: University hospital clinic.Patients: Forty-five diabetic patients with asymptomatic autonomic neuropathy identified by at least one pathologic cardiovascular reflex test result.Interventions: All patients were given placebo during a 4-week run-in period (single-blind). Twenty patients were randomly assigned to continue to receive placebo, and 25 were assigned to treatment with tolrestat (200 mg/d given in the morning).Measurements and Results: At 12 months, improvements in nerve functions occurred in patients receiving tolrestat. Compared with baseline values, postural hypotension decreased by a value of 5.9 mm Hg (95% Cl, 1.6 to 8.7); deep-breathing, maximum/minimum heart rate (expiration/inspiration ratio) increased by a value of 0.026 (Cl, 0.015 to 0.036); and lying-to-standing heart rate ratio (30:15 ratio) increased by a value of 0.032 (Cl, 0.027 to 0.052). In the placebo group, all test results except postural hypotension deteriorated. Vibration perception threshold at the malleolus and great toe of the dominant leg improved in the tolrestat group (-1.4; Cl, -3.69 to -1.09) but tended to worsen in the placebo group during the study period. No important side effects were detected in either group.Conclusions: The progression of mild diabetic autonomic and peripheral neuropathy may be halted or even reversed by pharmacologic intervention with the aldose-reductase inhibitor tolrestat. [ABSTRACT FROM AUTHOR]